This candidate has 3 career goals: (1) to be an outstanding clinician, (2) to be a leading scientist in patient-oriented research in liver disease, and (3) to train junior clinicians as biomedical scientists. He received a K24 award in 1999 to protect his time to foster the latter two career goals. During the last 4 years, the candidate made several new discoveries related to the pathogenesis of nonalcoholic steatohepatitis (NASH) and the role of endogeneous cannabinoids in portal hypertension. He has recently competitively renewed a T-32 training grant (DK 07150) and two of his trainees have become independently funded. This application for competitive renewal has been written to consolidate the gains made during the initial award period. Two research projects are proposed: (1) A NIH-funded clinical trial (DK 61731) of pioglitazone or vitamin E versus placebo for the treatment of NASH. This trial, developed in part from this candidates work, will test the hypothesis that both vitamin E and pioglitazone are superior to placebo for the treatment of NASH. Subjects with biopsy-proven NASH, who do not have diabetes or cirrhosis, will be enrolled in this double-dummy, placebo-controlled trial. The primary endpoint will be an improvement in the hepatic histology. (2) Studies of the impact of behavior on NASH, which will test the hypothesis that specific social and psychological factors contribute to the behavioral profile associated with NASH as well as the likelihood of success of treatment of NASH. This will be tested by studies with 3 specific aims: (a) to measure and quantify the behavioral characteristics of subjects with NASH and compare them to normal subjects and those with other liver diseases, (b) to determine the relationship between behavioral parameters and the physiologic and histologic abnormalities in NASH, and (3) to define the impact of behavioral parameters on compliance and success of treatment for NASH. Much progress has been made and supports the hypothesis. The institutional environment and facilities/resources are excellent for career development in academic medicine.